429 research outputs found
Insights into the control of taxane metabolism: Molecular, cellular, and metabolic changes induced by elicitation in Taxus baccata cell suspensions
More knowledge is needed about the molecular/cellular control of paclitaxel (PTX) production in Taxus spp. cell cultures. In this study, the yield of this anticancer agent in Taxus baccata cell suspensions was improved 11-fold after elicitation with coronatine (COR) compared to the untreated cells, and 18-fold when co-supplemented with methyl-β-cyclodextrins (β-CDs). In the dual treatment, the release of taxanes from the producer cells was greatly enhanced, with 81.6% of the total taxane content being found in the medium at the end of the experiment. The experimental conditions that caused the highest PTX production also induced its maximum excretion, and increased the expression of taxane biosynthetic genes, especially the flux-limiting BAPT and DBTNBT. The application of COR, which activates PTX biosynthesis, together with β - CDs, which form inclusion complexes with PTX and related taxanes, is evidently an efficient strategy for enhancing PTX production and release to the culture medium. Due to the recently described role of lipid droplets (LDs) in the trafficking and accumulation of hydrophobic taxanes in Taxus spp. cell cultures, the structure, number and taxane storage capacity of these organelles was also studied. In elicited cultures, the number of LDs increased and they mainly accumulated taxanes with a side chain, especially PTX. Thus, PTX constituted up to 50-70% of the total taxanes found in LDs throughout the experiment in the COR + β - CD-treated cultures. These results confirm that LDs can store taxanes and distribute them inside and outside cells. Keywords: Taxus baccata; cell cultures; coronatine; gene expression; lipid droplets; paclitaxel; taxane accumulation
Viability-reducing activity of Coryllus avellana L. extracts against human cancer cell lines
The increasing rate of cancer incidence has encouraged the search for novel natural sources of anticancer compounds. The presence of small quantities of taxol and taxanes in Corylus avellana L. has impelled new potential applications for this plant in the field of biomedicine. In the present work, the cell viability-reducing activity of stems and leaves from three different hazel trees was studied against three human-derived cancer cell lines (HeLa, HepG2 and MCF-7). Both leaf and stem extracts significantly reduced viability of the three cell lines either after maceration with methanol or using taxane extraction methods. Since maceration reduced cell viability to a greater extent than taxane extraction methods, we scaled up the maceration extraction process using a method for solid/liquid extraction (Zippertex technology). Methanol leaf extracts promoted a higher reduction in viability of all cell lines assayed than stem extracts. Fractionation of methanol leaf extracts using silica gel chromatography led to the purification and identification of two compounds by HPLC-MS and NMR: (3R,5R)-3,5-dihydroxy-1,7-bis(4-hydroxyphenyl) heptane 3-O-β-d-glucopyranoside and quercetin-3-O-rhamnoside. The isolated compounds decreased viability of HeLa and HepG2 cells to a greater extent than MCF-7 cells. Our results suggest a potential use of C. avellana extracts in the pharmacotherapy of cervical cancer and hepatocarcinoma and, to a lesser extent, breast cancer
Enantioselective organocatalytic asymmetric allylic alkylation. Bis(phenylsulfonyl)methane addition to MBH carbonates
The highly enantioselective asymmetric allylic alkylation of Morita-Baylis-Hillman carbonates with bis(phenylsulfonyl) methane is presented.The reaction is simply catalyzed by cinchona alkaloid derivatives affording the final alkylated products in good yields and enantioselectivities
Calculating Evolutionary Dynamics in Structured Populations
Evolution is shaping the world around us. At the core of every evolutionary process is a population of reproducing individuals. The outcome of an evolutionary process depends on population structure. Here we provide a general formula for calculating evolutionary dynamics in a wide class of structured populations. This class includes the recently introduced “games in phenotype space” and “evolutionary set theory.” There can be local interactions for determining the relative fitness of individuals, but we require global updating, which means all individuals compete uniformly for reproduction. We study the competition of two strategies in the context of an evolutionary game and determine which strategy is favored in the limit of weak selection. We derive an intuitive formula for the structure coefficient, σ, and provide a method for efficient numerical calculation
Mucoidy, Quorum Sensing, Mismatch Repair and Antibiotic Resistance in Pseudomonas aeruginosa from Cystic Fibrosis Chronic Airways Infections
Survival of Pseudomonas aeruginosa in cystic fibrosis (CF) chronic infections is based on a genetic adaptation process consisting of mutations in specific genes, which can produce advantageous phenotypic switches and ensure its persistence in the lung. Among these, mutations inactivating the regulators MucA (alginate biosynthesis), LasR (quorum sensing) and MexZ (multidrug-efflux pump MexXY) are the most frequently observed, with those inactivating the DNA mismatch repair system (MRS) being also highly prevalent in P. aeruginosa CF isolates, leading to hypermutator phenotypes that could contribute to this adaptive mutagenesis by virtue of an increased mutation rate. Here, we characterized the mutations found in the mucA, lasR, mexZ and MRS genes in P. aeruginosa isolates obtained from Argentinean CF patients, and analyzed the potential association of mucA, lasR and mexZ mutagenesis with MRS-deficiency and antibiotic resistance. Thus, 38 isolates from 26 chronically infected CF patients were characterized for their phenotypic traits, PFGE genotypic patterns, mutations in the mucA, lasR, mexZ, mutS and mutL gene coding sequences and antibiotic resistance profiles. The most frequently mutated gene was mexZ (79%), followed by mucA (63%) and lasR (39%) as well as a high prevalence (42%) of hypermutators being observed due to loss-of-function mutations in mutL (60%) followed by mutS (40%). Interestingly, mutational spectra were particular to each gene, suggesting that several mechanisms are responsible for mutations during chronic infection. However, no link could be established between hypermutability and mutagenesis in mucA, lasR and mexZ, indicating that MRS-deficiency was not involved in the acquisition of these mutations. Finally, although inactivation of mucA, lasR and mexZ has been previously shown to confer resistance/tolerance to antibiotics, only mutations in MRS genes could be related to an antibiotic resistance increase. These results help to unravel the mutational dynamics that lead to the adaptation of P. aeruginosa to the CF lung
Social Experiments in the Mesoscale: Humans Playing a Spatial Prisoner's Dilemma
Background: The evolutionary origin of cooperation among unrelated individuals remains a key unsolved issue across several disciplines. Prominent among the several mechanisms proposed to explain how cooperation can emerge is the existence of a population structure that determines the interactions among individuals. Many models have explored analytically and by simulation the effects of such a structure, particularly in the framework of the Prisoner’s Dilemma, but the results of these models largely depend on details such as the type of spatial structure or the evolutionary dynamics. Therefore, experimental work suitably designed to address this question is needed to probe these issues. Methods and Findings: We have designed an experiment to test the emergence of cooperation when humans play Prisoner’s Dilemma on a network whose size is comparable to that of simulations. We find that the cooperation level declines to an asymptotic state with low but nonzero cooperation. Regarding players ’ behavior, we observe that the population is heterogeneous, consisting of a high percentage of defectors, a smaller one of cooperators, and a large group that shares features of the conditional cooperators of public goods games. We propose an agent-based model based on the coexistence of these different strategies that is in good agreement with all the experimental observations. Conclusions: In our large experimental setup, cooperation was not promoted by the existence of a lattice beyond a residual level (around 20%) typical of public goods experiments. Our findings also indicate that both heterogeneity and a ‘‘moody’
How Schools Affect Student Well-Being: A Cross-Cultural Approach in 35 OECD Countries
A common approach for measuring the effectiveness of an education system or a school
is the estimation of the impact that school interventions have on students’ academic
performance. However, the latest trends aim to extend the focus beyond students’
acquisition of knowledge and skills, and to consider aspects such as well-being in the
academic context. For this reason, the 2015 edition of the international assessment
system Programme for International Student Assessment (PISA) incorporated a new tool
aimed at evaluating the socio-emotional variables related to the well-being of students. It
is based on a definition focused on the five dimensions proposed in the PISA theoretical
framework: cognitive, psychological, social, physical, and material. The main purpose
of this study is to identify the well-being components that significantly affect student
academic performance and to estimate the magnitude of school effects on the wellbeing
of students in OECD countries, the school effect being understood as the ability of
schools to increase subjective student well-being. To achieve this goal, we analyzed the
responses of 248,620 students from 35 OECD countries to PISA 2015 questionnaires.
Specifically, we considered non-cognitive variables in the questionnaires and student
performance in science. The results indicated that the cognitive well-being dimension,
composed of enjoyment of science, self-efficacy, and instrumental motivation, as well as
test anxiety all had a consistent relationship with student performance across countries.
In addition, the school effect, estimated through a two-level hierarchical linear model, in
terms of student well-being was systematically low. While the school effect accounted
for approximately 25% of the variance in the results for the cognitive dimension, only
5–9% of variance in well-being indicators was attributable to it. This suggests that the
influence of school on student welfare is weak, and the effect is similar across countries.
The present study contributes to the general discussion currently underway about the
definition of well-being and the connection between well-being and achievement. The
results highlighted two complementary concerns: there is a clear need to promote socioemotional
education in schools, and it is important to develop a rigorous framework for
well-being assessment. The implications of the results and proposals for future studies
are discussed.Spain Ministry of Science, Innovation and Universities
PSI2017-85724-P2E Estudios, Evaluaciones e Investigacion, S.
Heterogeneous Aspirations Promote Cooperation in the Prisoner's Dilemma Game
To be the fittest is central to proliferation in evolutionary games. Individuals
thus adopt the strategies of better performing players in the hope of successful
reproduction. In structured populations the array of those that are eligible to
act as strategy sources is bounded to the immediate neighbors of each
individual. But which one of these strategy sources should potentially be
copied? Previous research dealt with this question either by selecting the
fittest or by selecting one player uniformly at random. Here we introduce a
parameter that interpolates between these two extreme options.
Setting equal to zero returns the random selection of the
opponent, while positive favor the fitter
players. In addition, we divide the population into two groups. Players from
group select their opponents as dictated by the parameter
, while players from group
do so randomly irrespective of
. We denote the fraction of players contained in groups
and by
and , respectively. The
two parameters and
allow us to analyze in detail how aspirations in the
context of the prisoner's dilemma game influence the evolution of
cooperation. We find that for sufficiently positive values of
there exist a robust intermediate
for which cooperation thrives best. The robustness of
this observation is tested against different levels of uncertainty in the
strategy adoption process and for different
interaction networks. We also provide complete phase diagrams depicting the
dependence of the impact of and
for different values of , and contrast the
validity of our conclusions by means of an alternative model where individual
aspiration levels are subject to evolution as well. Our study indicates that
heterogeneity in aspirations may be key for the sustainability of cooperation in
structured populations
Modulating Pharmacokinetics, Tumor Uptake and Biodistribution by Engineered Nanoparticles
Inorganic nanoparticles provide promising tools for biomedical applications including detection, diagnosis and therapy. While surface properties such as charge are expected to play an important role in their in vivo behavior, very little is known how the surface chemistry of nanoparticles influences their pharmacokinetics, tumor uptake, and biodistribution.Using a family of structurally homologous nanoparticles we have investigated how pharmacological properties including tumor uptake and biodistribution are influenced by surface charge using neutral (TEGOH), zwitterionic (Tzwit), negative (TCOOH) and positive (TTMA) nanoparticles. Nanoparticles were injected into mice (normal and athymic) either in the tail vein or into the peritoneum.Neutral and zwitterionic nanoparticles demonstrated longer circulation time via both i.p. and i.v. administration, whereas negatively and positively charged nanoparticles possessed relatively short half-lives. These pharmacological characteristics were reflected on the tumor uptake and biodistribution of the respective nanoparticles, with enhanced tumor uptake by neutral and zwitterionic nanoparticles via passive targeting
Ontogenetic loops in habitat use highlight the importance of littoral habitats for early life-stages of oceanic fishes in temperate waters
General concepts of larval fish ecology in temperate oceans predominantly associate dispersal and survival to exogenous mechanisms such as passive drift along ocean currents. However, for tropical reef fish larvae and species in inland freshwater systems behavioural aspects of habitat selection are evidently important components of dispersal. This study is focused on larval Atlantic herring (Clupea harengus) distribution in a Baltic Sea retention area, free of lunar tides and directed current regimes, considered as a natural mesocosm. A Lorenz curve originally applied in socio-economics to describe demographic income distribution was adapted to a 20 year time-series of weekly larval herring distribution, revealing size-dependent spatial homogeneity. Additional quantitative sampling of distinct larval development stages across pelagic and littoral areas uncovered a loop in habitat use during larval ontogeny, revealing a key role of shallow littoral waters. With increasing rates of coastal change, our findings emphasize the importance of the littoral zone when considering reproduction of pelagic, ocean-going fish species; highlighting a need for more sensitive management of regional coastal zones
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